In the adult central nervous system (CNS), specialized cells called oligodendrocytes function to generate myelin sheaths that coat subpopulations of axons, forming the white matter of the brain. The myelin sheath functions to enhance signal conduction by neurons and is required for neuronal health. Defects in myelination or damage to CNS myelin is thought to be central to the impairment of normal brain function in many CNS disorders, including Multiple Sclerosis (Bruck, W. et al Curr Opin Neurol 18:221 (2005); Kieseier, B. C. et al Curr Opin Neurol 18:211 (2005); Lubetzki, C. et al Curr Opin Neurol 18:237 (2005)), spinal cord injury (Keirstead, H. S. et al J Neurosci 25:4694 (2005)), age-related dementia (Buckner, R. L. Neuron 44:195 (2004); Peters, A. J Neurocytol 31:581 (2002)); depression and bipolar disorders (Aston, C. et al Mol Psychiatry 10:309 (2005); Bartzokis, G. et al Neurobiol Aging 25:843 (2004); Lyoo, I. K. et al Compr Psychiatry 43:361 (2002); Moore, P. B. et al Br J Psychiatry 178:172 (2001); Silverstone, T. et al Bipolar Disord 5:53 (2003)), as well as many of the cognitive impairments following stroke (Inzitari, D. Stroke 34:2067 (2003); Jokinen, H. et al Eur J Neurol 11:825(2004); Wardlaw, J. M. et al Neurology 59:1381 (2002)).
The adult mammalian CNS contains oligodendrocyte precursor cells (OPCs) throughout both grey and white matter regions, which function to generate new oligodendrocytes throughout adulthood (Gensert, J. M. et al Glia 17:39 (1996); Levine, J. M. et al Trends Neurosci 24:39 (2001); Levison, S. W. et al J Neurosci Res 57:435 (1999); Lubetzki, C. et al Curr Opin Neurol 18:237 (2005)). As a result of OPC proliferation the number of oligodendrocytes increases in the adult rodent and primate brain with age (Ling, E. A. et al J Comp Neurol 149:73 (1973); Peters, A. J Neurocytol 31:581 (2002); Peters, A. et al Anat Rec 229:384 (1991)). Further, OPCs are thought to generate new oligodendrocytes in response to injury, which to a limited extent can remyelinate regions of myelin damage (Armstrong, R. C. et al J Neurosci 22:8574 (2002); Gensert, J. M. et al Glia 17:39 (1996); Stangel, M. et al Prog Neurobiol 68:361 (2002)). Presently, little is known about the physiological mechanisms that regulate endogenous OPC proliferation and oligodendrocyte generation in the adult CNS. However, the discovery of these mechanisms may have dramatic implications for the treatment of brain injury and disease through the development of methods to promote the proliferation of OPCs and the generation of new myelinating oligodendrocytes capable of repairing demyelinated CNS tissue (Levine, J. M. et al Trends Neurosci 24:39 (2001); Lubetzki, C. et al Curr Opin Neurol 18:237 (2005); Stangel, M. et al Prog Neurobiol 68:361 (2002)). Consequently, it is desirable to discover signaling molecules capable of promoting OPC proliferation such that these cells may be expanded either in vitro for transplantation or in vivo to promote endogenous white matter repair.